Abstract The management of chronic viral hepatitis C is evolving
rapidly. Monotherapy with interferon, the accepted standard of treatment
until recently, achieves only a modest sustained virological response
rate of 15%. Combination treatment with alpha-2b interferon and ribavirin
has been shown to increase sustained response rates to 40% in patients
who have never been treated with interferon and to 50% in those who have
relapsed following monotherapy with interferon. However, side effects,
which have led to the discontinuation of combination treatment in a significant
proportion of patients, must be carefully monitored. Treatment with interferon
alpha-2b and ribavirin has now been approved in Canada, but the selection
and monitoring of patients suitable for combination treatment requires
special expertise. Although improvements in current therapeutic options
may be possible with more frequent, higher doses or long-acting forms
of interferon together with ribavirin, low sustained response rates (i.e.,
below 30%) for patients with hepatitis C virus genotype 1 emphasize the
need for novel antiviral medications that will target the functional sites
of the HCV genome. [Contents]

Hepatitis C virus (HCV) is the most common of the recognized chronic
hepatitis viruses in Canada and the United States1 and is a major cause
of cirrhosis and hepatocellular carcinoma. The prevalence of hepatitis
C infection in Canada is estimated to be between 0.5% and 1.2%.2,3 The
disease often remains asymptomatic for prolonged periods, but cirrhosis
may develop insidiously in 20%30% of chronically infected
individuals over a period of 2030 years.46 hepatitis
C related cirrhosis has become the leading indication for liver transplantation
in many transplant centres in North America. There are no effective vaccines
available for HCV. Hepatitis C virus is a single-stranded RNA virus that
belongs to the flaviviridae family.7 The structural and functional proteins
of the HCV genome have been well characterized over the past 10 years.

Of the 6 major HCV genotypes, genotype 1 is the most common; genotypes
2 and 3 are found in approximately 10%20% of patients with
hepatitis C in North America. Novel antiviral agents that target the functional
sites of HCV are currently being developed.7 In this review we examine
how the presently available agents have changed the management of patients
with hepatitis C. In the past, treatment was limited to monotherapy with
various types of interferon (i.e., interferon alpha-2a, interferon alpha-2b
and consensus interferon) that have similar immunomodulatory and antiviral
effects. Monotherapy achieves viral clearance in only 15%20%.8,9
The nucleoside analogue ribavirin has recently been evaluated in combination
with interferon alpha-2b, and this combination of antiviral agents has
markedly improved the sustained virological response. The possible responses
to antiviral therapy are defined in Table 1 and will be referred to throughout
this review. Ribavirin as a single agent enhances a type-1 cytokine-mediated
immune response but does not suppress viremia levels; when given in combination
with interferon synergistic antiviral effects are seen (Fig. 1).10 [Contents]

Diagnosis of chronic viral hepatitis C The most practical screening tests
for hepatitis C virus antibodies are second- and third-generation enzyme
immunoassays (Table 2). The presence of HCV antibodies is usually confirmed
by a more specific recombinant immunoblot assay. All patients positive
for HCV antibodies by enzyme immunoassay and positive or indeterminate
by recombinant immunoblot assay should be tested for HCV RNA by qualitative
polymerase chain reaction to confirm chronic infection. Failure to detect
HCV RNA at this stage may be related to the sensitivity of the assay,
intermittent viremia or degradation of HCV RNA after sampling, or it may
mean that the test is actually negative. Only 10%20% of patients
with acute hepatitis C eventually clear HCV infection.1113
A negative polymerase chain reaction should therefore be repeated, especially
if there are abnormal liver enzymes present. In immunocompromised patients
anti-HCV antibodies by enzyme immunoassay may be absent despite viremia
in up to 10% of patients,14 and these patients should be tested primarily
by polymerase chain reaction if there is clinical suspicion of HCV infection.
The viral genotype should be determined in patients undergoing combination
antiviral treatment because treatment for patients with genotypes 2 and
3 can be shortened from 12 months to 6 months. The benefit of additional
HCV RNA quantitation for the determination of treatment duration is not
well defined; this test is therefore not routinely recommended at present.
However, knowing the viral load does help to predict the likelihood of
treatment response; a viral load 2 ×× 106 copies/mL is predictive
of reduced treatment response rates, especially in patients with genotype
1.15,16 [Contents]

Assessment of patients with chronic viral hepatitis C Patients with HCV
infection should be assessed for the severity of chronic liver disease
and for coexisting medical conditions.17 Signs and symptoms of chronic
liver disease and, in particular, decompensated liver disease (i.e., jaundice,
ascites, encephalopathy or bleeding from esophageal or gastric varices)
should be investigated. Patients with suspected advanced liver disease
should be offered a gastroscopy to screen for esophageal varices.18 If
small varices are identified patients should be screened yearly, and if
grade 2 or grade 3 varices are present a beta-blocker for the primary
prevention of bleeding should be initiated.18 Patients with cirrhosis
should be offered screening for hepatocellular carcinoma.19,20 However,
the current screening methods, alpha-1 fetoprotein determination and ultrasound
every 6 months, have sensitivities of only 50% and 70%, respectively,
and curative therapy through resection or liver transplantation is possible
in only a fraction of patients.21 Patients with advanced or decompensated
liver disease should be referred for an assessment for liver transplantation.
hepatitis C virtually always recurs after liver transplantation and may
cause cirrhosis and loss of the hepatic allograft. Nevertheless, the short-
and medium-term survival of up to 5 and 8 years, respectively, is similar
to patients who receive a liver transplant for other reasons.2224
Lifestyle risk factors such as alcohol consumption and intravenous drug
use should be reviewed with patients. In particular, the need to abstain
from alcohol use must be emphasized because alcohol is a significant risk
factor for the progression of chronic viral hepatitis C. Patients at risk
for recidivism should consider enrolling in a drug or alcohol rehabilitation
program before antiviral treatment is initiated.2527 Coexisting
viral, autoimmune, metabolic or drug-induced liver disease should be ruled
out (Table 3). Patients should also be examined for extrahepatic manifestations
of hepatitis C (e.g., porphyria cutana tarda or mixed essential cryoglobulinemia).
A liver biopsy is recommended for the majority of patients with elevated
liver enzymes or clinical evidence of early cirrhosis. A biopsy will help
to identify patients at higher risk for disease progression so they can
be treated, as well as those with otherwise unrecognized coexisting liver
disease.28,29 In patients with normal alanine aminotransferase levels
liver enzymes should be repeated at least 3 times in a 6-month period
to ensure they remain normal and at least yearly thereafter.30 [Contents]

Management of patients with chronic hepatitis C All patients should be
informed of the natural progression of the disease, measures to prevent
viral transmission and treatment options, including the risks and benefits
of antiviral therapy. Immunization against both hepatitis A and hepatitis
B is recommended because people with chronic liver disease may be at increased
risk for fulminant hepatitis A or B, and coinfection with hepatitis B
is associated with a greater risk of disease progression and hepatocellular
carcinoma.31,32 Among the many factors that influence the decision to
treat or not is the severity of the disease, likelihood of response to
treatment, concomitant medical problems, age of the patient and contraindications
for the use of interferon or ribavirin (Table 4). Treatment with interferon
and ribavirin is recommended for patients with confirmed HCV infection
who are expected to benefit from antiviral therapy after a complete clinical
assessment and review of the contraindications has been completed.

Combination treatment should be considered for patients with elevated
liver function tests who have never been treated with interferon (interferon
naïïve) and for those who have relapsed after an initial response
to monotherapy with interferon.

Patients at greatest risk for disease progression (e.g., those with evidence
of moderate inflammation or fibrosis on liver biopsy) should be given
treatment priority. For patients with normal liver enzymes or for those
in which aminotransferase levels failed to return to normal or HCV RNA
failed to clear during monotherapy with interferon (nonresponders), treatment
is currently not recommended outside clinical trials. Retreatment of nonresponders
with interferon monotherapy results in response rates below 15%, and combination
treatment with interferon alpha-2b and ribavirin for 6 months seems not
to improve sustained response rates.3337 Interferon treatment
of patients with advanced cirrhosis can be associated with severe side
effects and is contraindicated for patients with decompensated cirrhosis.38,39
On the basis of the side effect profiles (Table 5), interferon and ribavirin
are contraindicated if a patient has certain coexisting medical conditions.
Because ribavirin can produce significant embryotoxic or teratogenic effects
in several animal species and has a prolonged washout period from intracellular
compartments,40 strict compliance with contraceptive methods is required
during and for 6 months after therapy for all patients. Monotherapy with
interferon alpha-2b or other interferons, should be reserved for patients
who cannot tolerate ribavirin. Dosing schedules of interferons and long-acting
pegylated interferons, alone and combined with ribavirin or other antiviral
agents, are still being investigated; these combinations should not be
offered outside clinical trials or centres with special expertise.41,42
Patients with normal alanine aminotransferase levels Approximately 25%
of patients with chronic HCV infection have persistently normal alanine
aminotransferase levels.43,44 Liver biopsies indicate some degree of chronic
hepatitis in the majority of these patients, but fibrosis or cirrhosis
is less common.30,45

Serfaty and colleagues46 reported that monotherapy with interferon resulted
in lower sustained response rates in patients with normal liver enzyme
levels than in those with elevated levels. More importantly, treatment-induced
elevations of liver enzymes have also been observed, and the underlying
liver disease might be exacerbated if the relationship between viral replication
and the host immune response is altered.46,47 Treatment with interferon
is therefore not recommended, and combination treatment with interferon
and ribavirin has not been studied in these patients yet.17 Asymptomatic
patients without stigmata of chronic liver disease should be reviewed
periodically because treatment strategies may change as more effective
antiviral agents with fewer side effects become available in the future.
Interferon-naïïve patients with elevated alanine aminotransferase
levels Until recently, monotherapy with 3 million IU interferon 3 times
per week for 12 months was the accepted standard of treatment for patients
with elevated liver enzymes and at least moderate neuroinflammatory activity
or fibrosis on liver biopsy.17 Normalization of aminotransferase levels
and the disappearance of serum HCV RNA has been reported in about 40%
of patients at the end of such treatment; however, a sustained virological
response was achieved in only 15%20% of patients.8,9 There
is accumulating evidence that the sustained virological response, when
achieved, is durable and prevents the progression of disease.48,49 Combination
antiviral treatment with interferon alpha-2b and ribavirin was evaluated
recently in 2 large, randomized, placebo-controlled clinical trials.15,16
Only patients with elevated liver enzymes over a 6-month period and with
confirmed HCV infection by polymerase chain reaction and liver biopsy
were included in the trials; those with significant coexisting medical
conditions or decompensated cirrhosis were excluded from both studies.
Most patients had HCV genotypes 1, 2 or 3, and a few patients had cirrhosis
on the pretreatment liver biopsies. In the US multicentre trial 912 patients
were randomized to receive interferon alpha-2b and ribavirin or interferon
alpha-2b and placebo for 24 or 48 weeks.16 In the international trial
832 patients were randomized as in the US trial, but there was no 24-week
interferonplacebo group.15 The dosage for interferon alpha-2b
was 3 million IU subcutaneously 3 times per week; ribavirin was given
orally and adjusted for the patient's weight (i.e., 1000 mg for patients
75 kg). Main outcome measures in the 2 studies were sustained virological
response rates (i.e., undetectable serum HCV RNA 6 months after treatment)
and histological improvement 24 weeks after treatment when compared with
the pretreatment liver biopsy. Patients were stratified according to pretreatment
variables known to influence interferon response (i.e., genotype, viral
load and presence or absence of cirrhosis). The results of these trials
expand on those of earlier smaller trials5052 and have changed
our current treatment strategies. Both studies reported that the rate
of sustained virilogical response was higher for patients who received
an interferon alpha-2b plus ribavirin combination for 48 weeks than for
those who received interferon alone.15,16 Reduced efficacy was associated
with HCV genotype 1, a baseline viral load of 2 ×× 106 copies/mL,
the presence of cirrhosis, age above 40 years and male sex.15,16 Patients
with HCV genotypes 2 and 3 showed a 64%69% sustained response
rate after 24 weeks of combination therapy, and extending therapy to 48
weeks did not increase response rates irrespective of the viral load.15,16
However, patients with HCV genotype 1 and high viral titers or cirrhosis
did achieve a higher sustained virological response rate with 48 weeks
of treatment than with 24 weeks.15,16 All groups showed histologic improvement;
however, it was more common in the 48-week combination group than in the
24-week combination and interferon monotherapy groups. Although viral
genotype 1 and high viral load are predictors of poorer response, patients
should not be excluded from treatment because up to 28% of these patients
may still obtain a sustained virological response.15 Combination therapy
was discontinued for adverse events in 8% and 19% of patients in the 24-
and 48-week treatment groups, respectively.15 Dose reduction or discontinuation
for adverse effects was more common in patients receiving combination
therapy. The most common reason for dose reduction was anemia15,16 and
for discontinuation, depression.16 Hence, careful laboratory and clinical
monitoring throughout the treatment period is required, and physicians
should be familiar with indications, contraindications and side effects
of combination antiviral therapy. Patients previously treated with interferon
monotherapy who relapsed Roughly half of the patients who are treated
successfully with interferon monotherapy will relapse after treatment
is stopped.8 Most of these patients will respond to a second course of
interferon, but higher than standard doses of interferon and treatment
periods longer than 1 year or treatment with consensus interferon is required
to achieve a sustained response in 20%50% of patients.33,34,53
Combination treatment with interferon alpha-2b and ribavirin for 24 weeks
has recently been shown to result in a sustained virological response
in 49% of relapsers compared with only 5% of those treated with standard
doses of interferon a second time;54 sustained response rates varied between
100% (for patients with genotypes other than 1 and a baseline viral load
¾¾ 2 * 106 copies/mL) and 25% (for patients with genotype
1 and a baseline viral load 2 ×× 106 copies/mL). Hence, patients
who have relapsed after interferon monotherapy should be offered combination
treatment. Whether combination treatment beyond 6 months will increase
sustained virological response rates in relapsed patients with unfavorable
response factors remains to be determined. [Contents]

Monitoring of therapy and follow-up Close clinical and laboratory monitoring
is required throughout the treatment period.17 Most patients receiving
interferon experience influenza-like symptoms, which diminish with continued
treatment. Later side effects include bone marrow suppression, thyroid
abnormalities and neuropsychiatric effects (Table 5).8,55 Ribavirin predictably
induces hemolytic anemia, which may be especially severe in patients with
preexisting bone marrow suppression and can be life threatening for patients
with significant cardiovascular or cerebrovascular disease. The hemoglobin
usually falls in the first 24 weeks of treatment and then
stabilizes in most patients. Complete blood counts with differential should
be measured at least every 2 weeks in the first months of treatment and
then monthly, and liver function tests should also be done monthly. Thyroid
function tests and a urinanalysis should be done every 3 months. Following
treatment a sensitive, qualitative polymerase chain reaction assay for
HCV RNA should be performed, and liver enzymes should be assessed at 6
or 12 months. Failure of serum alanine aminotransferase levels to return
to normal or HCV RNA to clear by 3 months was a strong predictor of interferon
monotherapy treatment failure.5658 However, some patients
with cirrhosis or steatosis may continue to have abnormal liver enzyme
levels despite a virological response. There is conflicting data from
clinical trials that evaluated combination treatment with regard to the
predictive value of early viral clearance. In one study16 up to 14% of
patients who were positive for HCV RNA by polymerase chain reaction at
3 months eventually became sustained responders; however, patients who
failed to clear by 6 months did not achieve a sustained virological response.16,54
Hence, treatment should be discontinued if there is no clearance of HCV
RNA by polymerase chain reaction after 6 months. There is currently no
known effective treatment for those who do not respond to combination
therapy. However, these patients should be followed clinically for the
progression of liver disease and should be considered for new treatment
protocols. Sustained virological responders are likely to maintain their
improved histology and may be at reduced risk for hepatocellular carcinoma.25,59,60
Nevertheless, a small fraction will relapse, and patients with cirrhosis,
in particular, will still be at risk for hepatocellular carcinoma even
after viral clearance. Therefore, all patients should continue to be followed,
and screening for hepatocellular carcinoma should be offered to those
with cirrhosis.61